pooled mutant kras-targeted long peptide vaccine combined with nivolumab and ipilimumab for patients with resected mismatch repair protein (mmr-p) colorectal and pancreatic cancer

Conditions: Colorectal Cancer; Pancreatic Cancer

Summary: phase 1 study for patients with resected pdac after neoadjuvant and/ or adjuvant chemotherapy and/or radiation, as well as patients with metastatic colorectal cancer who have exposure to 2 or more lines of chemotherapy, to evaluate safety and the immune response to pooled mutant-kras peptide vaccine (kras peptide vaccine) with poly-iclc adjuvant in combination with nivolumab and ipilimumab.


Eligibility criteria:
inclusion criteria: pdac or metastatic mss crc cohort: * have histologically or cytologically - proven cancer of the pancreas (pda) or mss colorectal (crc) in one of the following categories: * pdac must have no evidence of disease and last dose of neoadjuvant and/or adjuvant chemotherapy/radiation therapy/or surgery must be \< 6 months from study entry. * metastatic mss crc after exposure to 2 more lines of chemotherapy in the metastatic setting including 5-flurouracil, irinotecan, and oxaliplatin exposure. patients treated with folfoxiri may enroll after progression or intolerance to that regimen. * for metastatic mss crc cohort, must have tumor lesions amenable to repeated biopsy, and patient's acceptance to have a tumor biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the principal investigator). * for metastatic mss crc patients, must have measurable disease per recist 1.1. reinduction treatment cohort: * have a single site of locoregional recurrence or distant metastasis noted on imaging \> 12 months after the first dose of the mutant kras peptide vaccine with poly-iclc adjuvant. * have completed definitive treatment for solitary recurrence per standard-of-care (e.g. surgical resection, radiation, and/or chemotherapy) \<6 months prior to screening for reinduction treatment. both cohorts: \*age ≥18 years. * have sufficient archival tumor tissue for next-generation sequencing (ngs) and immune-phenotyping. * have one of the kras mutations included in the vaccine at the time of vaccination expressed in tumor. * eastern cooperative oncology group (ecog) performance status 0 or 1 * life expectancy of greater than 6 months. * patients must have adequate organ and marrow function defined by study-specified laboratory tests prior to initial study drug. * woman of childbearing potential must have a negative pregnancy test and follow contraceptive guidelines as defined per protocol. * men must use acceptable form of birth control while on study. * ability to understand and willingness to sign a written informed consent document. exclusion criteria * if expected to require any other form of systemic or localized antineoplastic therapy while on study. * within 2 weeks prior to first dose of study drug. * systemic or topical steroids corticosteroids at immunosuppressive doses (\> 10 mg/day of prednisone or equivalent). inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. * any palliative or adjuvant radiation or gamma knife radiosurgery. * any chemotherapy. * within 4 weeks prior to first dose of study drug. * any investigational cytotoxic drug. * any investigational device. * has received a live vaccine. * received any allergen hyposensitization therapy. * received any growth factors, e.g. granulocyte-colony stimulating factor (g-csf), granulocyte macrophage-colony stimulating factor (gm-csf), erythropoietin. * any major surgery. * pdac or metastatic mss crc cohort: prior treatment with immunotherapy agents (including, anti-pd-1, anti-pd-l1, anti-pd-l2, anti-cytotoxic t-lymphocyte-associated protein 4 (ctla4), etc.). * hypersensitivity reaction to any monoclonal antibody. * known history or evidence of brain metastases. * has active autoimmune disease that has required systemic treatment in the past 2 years, or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. * known history or concurrent interstitial lung disease. * has a pulse oximetry \< 92% on room air. * requires the use of home oxygen. * infection with hiv or hepatitis b or c. * uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness/social situations that would limit compliance with study requirements. * has been diagnosed with another cancer or myeloproliferative disorder within the past 5 year. * has a diagnosis of immunodeficiency. * presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. patients with a history of allogeneic hematopoietic stem cell transplant will be excluded. * any other sound medical, psychiatric, and/or social reason as determined by the investigator. * unwilling or unable to follow the study schedule for any reason. * are pregnant or breastfeeding. * for metastatic mss crc and reinduction treatment cohorts, any peritoneal involvement by the tumor. * for metastatic mss crc and reinduction treatment cohorts, any radiological or clinical pleural effusions or ascites. * for metastatic mss crc and reinduction treatment cohorts, patients on parenteral nutrition. * for metastatic mss crc and reinduction treatment cohorts, patients with any single liver metastases greater than 5 cm or greater \> 50% liver involvement. * for metastatic mss crc and reinduction treatment cohorts, history of malignant bowel obstruction.

Keywords: kras peptide vaccine nivolumab ipilimumab anti-pd-1 anti-ctla-4 neoantigen vaccines cancer vaccines immunotherapy colon cancer pancreatic ductal adenocarcinoma (pdac) resected mmr-p colorectal cancer resected mmr-p pancreatic cancer